In order to examine the compatibility of a carbon bridge for restricting the conformation of the pyroglutamate region of the thyrotropin-releasing hormone (thyroliberin, TRH) with binding and activation of the TRH receptor (TRH-R), the conformationally restricted TRH analog 3 was synthesized and tested for binding, potency, and efficacy. By taking advantage of an electrochemical procedure for functionalizing pyroglutamate derivatives, analog 3 was synthesized in just six steps from pyroglutamic acid. The testing of 3 for its ability to activate TRH-R showed that the carbon bridge added to restrict the conformation of the pyroglutamate region did not seriously interfere with either binding or activation. It is clear from this work that the added carbon bridge is suitable for use in "mapping" the three-dimensional requirements of the TRH-R binding site.